Drug self-administration research consistently suggests the importance of CNS dopamine (DA) and the dopamine transporter (DAT) in stimulant abuse. In our ongoing research with DAT ligands, we have found several compounds that are as effective as cocaine in blocking DA uptake in vitro but are, at most, weak positive reinforcers. The present proposal describes research designed to help elucidate this apparent disconnect between DAT actions and reinforcing effects. The proposed research will increase our understanding of the pharmacological and behavioral mechanisms that determine whether and to what extent drugs that block DA uptake can control behavior. Specific Aim 1 is to examine the contribution of non-DA actions of transporter ligands to their reinforcing effects. Our general hypothesis is that the mix of DA/5-HT/NE actions, rather than DA action exclusively, determines the reinforcing effects of stimulants. More specifically, we hypothesize that at a given level of 5-HT/DA selectivity, reinforcing efficacy varies with NE selectivity. Further, we hypothesize that at a given level of NE/DA selectivity, reinforcing efficacy varies with 5-HT selectivity. We propose to test this hypothesis by evaluating in rhesus monkeys the reinforcing effects of novel compounds selected to vary in their mix of DA, NE and 5-HT transporter actions. Pharmacokinetics may also contribute to between-drug differences in reinforcing efficacy: more rapid onset of action has been associated with enhanced reinforcing efficacy. Specific Aim 2 is to study the relationship between rate of DAT occupancy and reinforcing effect. We hypothesize that a more rapid onset of action of a DAT ligand is associated with greater efficacy as a reinforcer. We will relate the relative reinforcing efficacy of transporter ligands to the rate of transporter occupancy as measured using ex vivo binding assays. In addition to reinforcing effects, a drug may act as a punisher to suppress its own self-administration. Specific Aim 3 is to investigate CNS actions that may mediate punishing effects of drugs using a novel technique involving choice between injections delivered simultaneously with a positive reinforcer, food. We predict that delivery of food and a punishing drug will divert choice from the food+drug option to preference for the food+saline option. We will investigate the role of monoamine and several other neurotransmitter systems in drug punishment. The proposed research will expand our consideration of mechanisms by which drug consumption can control behavior. The ability to distinguish between positive, neutral and punishing drug effects will enhance our understanding of the basic neurobehavioral biology of drug abuse and may, by extension, have implications for our understanding of the physiology of affect and mood.